CN102811681A

CN102811681A - Methods of conditioning sheet bioprosthetic tissue

Info

Publication number: CN102811681A
Application number: CN2011800154540A
Authority: CN
Inventors: J·S·德夫; B·田; R·施奈德; J·S·科恩; I·扬科维奇; J·F·米利亚扎; G·A·莱特; J·M·杨; L·A·坎贝尔
Original assignee: Edwards Lifesciences Corp
Current assignee: Edwards Lifesciences Corp
Priority date: 2010-03-23
Filing date: 2011-03-23
Publication date: 2012-12-05
Anticipated expiration: 2031-03-23
Also published as: US20220117730A1; US8846390B2; EP2549957A4; EP2656863A2; EP2674174A3; AU2011232510A1; US20170071731A1; BR122014006918A2; EP2674174B1; BR122014006876B1; CA2794121A1; CA2794121C; US20130116676A1; EP2674174A2; CN102811681B; BR112012023769A2; US9492230B2; BR122014006876A2; US10092399B2; US9498288B2

Abstract

Methods for the conditioning of bioprosthetic material employ bovine pericardial membrane. A laser directed at the fibrous surface of the membrane and moved relative thereto reduces the thickness of the membrane to a specific uniform thickness and smoothes the surface. The wavelength, power and pulse rate of the laser are selected which will smooth the fibrous surface as well as ablate the surface to the appropriate thickness. Alternatively, a dermatome is used to remove a layer of material from the fibrous surface of the membrane. Thinning may also employ compression. Stepwise compression with cross-linking to stabilize the membrane is used to avoid damaging the membrane through inelastic compression. Rather, the membrane is bound in the elastic compressed state through addition cross-linking.; The foregoing several thinning techniques may be employed together to achieve strong thin membranes. The finally thinned membrane may then be treated by capping of calcification nucleation sites and borohydride reduction. The leaflets may be formed to have more than one region of uniform thickness, such as a thicker peripheral sewing region.

Description

Regulate the method for lamellar bioprosthetic tissue

Related application

The application requires the priority of U.S. Provisional Application serial number of submitting on March 23rd, 2,010 61/316,801 and the U.S. Provisional Application serial number of submitting on JIUYUE 10th, 2,010 61/381,858 according to 35U.S.C. § 119 (e).

Invention field

The field of the invention is to regulate the bioprosthetic tissue be used for implant, more specifically, be make the lamellar bioprosthetic tissue polish with attenuation to be used for the method for Cardiac valve prosthesis.

Background of invention

Medical skill for a long time can be through the impaired or ill cardiac valve of cardiac operation under direct vision displacement.This valve comprises machinery and is used to from those of the biomaterial of people's (homotransplantation tissue) and animal (xenograft tissues).The Cardiac valve prosthesis of two kinds of main types as known in the art is mechanical valve prosthesis and bioprosthesis valve.The bioprosthesis valve can by complete, many lobules pig (porcine, pig) cardiac valve forms, or through plastotype from a plurality of independent flexible leaflets of cattle pericardium tissue or other material and make up lobule and form with the formation valve.Different with mechanical valve prosthesis, an advantage of bioprosthesis valve is that the patient who receives valve need not use the anticoagulant long-term treatment usually.

Pericardium is the capsule around the vertebrates heart, and it contains lubricating fluid, and cattle (cow) pericardium is generally used for the valvular independent lobule of manufacture of intraocular.At first from animal, obtain bovine pericardium, then that it is chemically fixing, with tissue in collagen protein with elastin laminin is molecule crosslinked and raising tissue tolerance, be cut into lobule then.

At Simionescu etc.; Mapping of Glutaraldehyde-Treated Bovine Pericardium and Tissue Selection For Bio-prosthetic Heart Valves, Journal of Bio-Medical Materials Research, Vol.27; 697-704; John Wiley &Sons, Inc. provides the penetrating argumentation about the various physical properties of fixed bovine pericardium in 1993.Simionescu etc. recognize the pericardium tissue, even the significant change frequently of the physical property of identical pericardial sac.

Pericardial sac is made up of two kinds of different component of organization.Visceral layer or slurry layer are to approach translucent tissue heart, extremely thin most, and it is not used in and makes up the Cardiac valve prosthesis lobule.The internal layer of pericardium is taper, and it is around the root of heart and trunk.The body wall pericardium is to have the thicker film of multilamellar with the connective tissue of fatty tissue covering.When being obtained, the fat/fatty tissue of outside is removed (for example, peeling off).Remaining multi-layer fiber is organized and is mainly contained collagen fabric, and it has general fiber outer surface and slippery inner surface.Remaining film is used to the valvular lobule of manufacture of intraocular.

In some step examples of the typical commercial method of the pericardium tissue that is used for preparing heart valve leaflets in Fig. 1.At first, fresh pericardial sac 20 is available from regular slaughterhouse.Then, cut capsule 20 along predetermined anatomic landmarks---shown in 22---.Then, capsule is flattened 24, and removes unnecessary fat and other impurity usually.After the obviously useless zone of finishing, the window of tissue (window) 26 is fixed---usually through be immersed in the aldehyde with organize crosslinkedly, isolated about 2 weeks then.Usually, can obtain two windows on a face from a cattle pericardial sac---4 to 6 inches.The Roughen Edges of window 26 is organized in removal, and, tissue is carried out biology selection (bio-sorted), to produce tissue slice (section) 28.The process of biological selection relates to the useless region of manhole 26 visually, and therefrom finishing section 28.Subsequently, section 28 further is cleaned, shown in 30.

Then, will cut into slices 28 lies on the platform 32, carries out thickness measure to utilize contact indicator (contact indicator) 34.Through move at random around platform 32 section 28 simultaneously the axle 36 of indicators 34 move up and down at each point and measure thickness.The thickness of each point is presented at 38 places, and by operator's record.After section 28 selections that will measure through thickness, as shown in 40, die-cut lobule 42 from section wherein, be generally used for less valve than lobulus gracilis 42, and thicker lobule is used for bigger valve.Certainly, this method is time-consuming relatively, and the quality of final lobule depends on technician's in some steps technical ability.In addition, from each win the lobule number be inconsistent, it receives some invalid influences of manual selection course.A solution of the manual method that this is time-consuming is provided at the U.S. Patent number 6 of Ekholm etc.; 378; In 221, wherein, three programmable controllers are with respect to thickness measure head (measurement head) operation pericardium sheet; On landform, the similar thickness district, sheet is located, be used for using after a while.Yet, promptly using advanced method, the changeableness of bovine pericardium also can cause can be used for the extremely low productive rate of the sheet of heart valve leaflets, and the every capsule of average out to is less than 2.

Typically, the cattle pericardium tissue thickness scope of acquisition is to 700 microns, although most materials thickness is between the 300-700 micron on 250 microns.

Utilize the valve of flexible leaflets, those as processing by cattle pericardium tissue, more important in the later stage, because these valves can be implanted through the method except that cardiac operation under direct vision.That the valve utilization connects is pliable and tough (for example, pericardium) but the support of the radial dilatation of lobule makes up.Implantation method comprises with tangible amount radial compression valve, to reduce its diameter or to send section (delivery profile), valve is inserted into means of delivery, like conduit or intubate, and means of delivery is pushed to the correct anatomical location in the heart.After suitably arranging, valve launches in the natural valve ring through radial dilatation---perhaps perhaps utilize expanded balloon through the self expandable supporting structure.Folding valve can be through vascular system such as through femoral artery or more directly in the conduit, and the intercostal otch through in the heart is introduced into.Do not needing cardiac operation under direct vision, and possibly in operation process, need not stop to accomplish this program under the situation of heart.

An instance of percutaneous cardiac valve delivery is Cribier and Edwards Lifesciences of Irvine, the U.S. Patent number 6,908,481 of CA, and its demonstration has the false organ of valve of expansible framework, and collapsible valve property structure is installed on this framework.Other compressible/expansible cardiac valve is presented at U.S. Patent Publication number 2010/0036484In, it is also from Edwards Lifesciences.The further instance of this method and apparatus is disclosed in U.S. Patent number 7,621,948 with U.S. Patent Publication number 2006/0259136 in, and the number of other structure of this valve increases sharply along with the growth of technical prospect.The disclosure of each piece all is merged in this paper by reference in these lists of references.

The assembly that these new matching requirements are thin, this assembly can make valve be curled into downwards can be through the size of means of delivery.A restricted key element is the thickness of bioprosthetic tissue.As described, pericardium layer scope is the 250-700 micron, but only the pericardium of sub-fraction acquisition approaches low side, and low side is the most useful for the compressible/expansible valve.

U.S. Patent number 7,141,064 proposes the compression bovine pericardium, it is about 50% that its thickness is reduced, to be used for heart valve leaflets.Compression also can make tissue surface level and smooth, to reduce thickness offset.

Although to various bioprosthetic tissue, in particular for the various bioprosthetic tissue of heart valve leaflets a lot of researchs are arranged, but still need thin to be used to make the less bioprosthesis of sending section with the tissue of thickness more.

Summary of the invention

The present invention relates to be used for the preparation of the bioprosthetic material that the heart implants.Selection has the cattle pericardium of fiber surface and smooth surface.This method for preparing can improve the productive rate of the cardiac valve leaflet of pericardium, and can eliminate the thrombosis agent, as the fiber that dangles (dangling fiber).

According to an aspect, the method for preparing the bioprosthetic tissue membrane material comprises: tissue film's (for example, cattle pericardium) of at first selecting to have fibrous face and shiny surface.Then, remove material from the fibrous face of the film selected, to reduce film thickness and to make fibrous face smooth.Material can be removed through shearing with machinery such as dermatotome or vibratome (vibratome).Alternatively, material can be through being removed with laser ablation.

In described method just now, the tissue film that the film of selection can be selected through compression and make simultaneously under compression that membrane material is crosslinked to be conditioned.In addition, this method can comprise through adding medicated cap calcification nucleation site and/or handling the film that thickness reduces through borohydride reduction.According to an aspect, this method also is included in removes before the step film that partial fixing is at least selected.

According to another method as herein described; The bioprosthetic tissue membrane material is produced as follows: at first; Selection has the tissue film of fibrous face and shiny surface; Through compression and in the following simultaneously cross linking membrane tissue film that regulates selection of compression, remove the material that is conditioned from the fibrous face of the tissue film selected then, to reduce film thickness and fibrous face is polished.Tissue film can be a pericardium, like cattle or horse.This method can comprise through adding medicated cap and/or handling the film that thickness reduces through borohydride reduction.According to an aspect, remove step and accomplish through shearing with machinery such as dermatotome or vibratome.Perhaps, removing step accomplishes through the material that is conditioned with laser ablation.

According to another aspect, the method for preparing the bioprosthetic tissue membrane material comprises: at first, select to have the tissue film of fibrous face and shiny surface.Membrane material is partial cross-linked at least, is poured second cross-linked material with chain length then, with domain between the excessive fibril of permissibility.Subsequently, tissue film at least partly is compressed.Tissue film can be the cattle pericardium.This method also can be included in the film of partial cross-linked at least film mild compression selection before.This method can comprise through adding medicated cap and/or handling the film that thickness reduces through borohydride reduction.According to an aspect, remove material from the fibrous face of the tissue film of mild compression.

Another aspect of the application is a cardiac valve; It comprises a plurality of lobules; Each lobule forms by lamellar structure, and said lamellar structure has first area with uniform first thickness and the second area with uniform second thickness, and said second thickness is greater than said first thickness.Preferred each lobule all has the cusp edge relative with free edge, and second area extends along cusp edge with the overall evenly band of width.Second area also can extend with the band of the overall evenly width free edge along each lobule.In addition, second area can radially extend to cusp edge from the center of free edge with the overall evenly band of width.Desirably, the transition of thickness is gradually between first and second zones.In one embodiment, cardiac valve comprises support frame, be connected with it with the neighboring of stitching thread lobule, and second area extends along leaflet edge, and stitching thread is through this leaflet edge.

Of the present invention first separately aspect, dermatotome is used to the fiber surface of film and moves with respect to it, so that smooth surface and/or film thickness is reduced to specific uniform thickness for example is not more than 250 microns.Dermatotome receives spacer (spacer) restriction, with remaining film thickness behind the material of control removal pruning.

Of the present invention second separately aspect, remove the fiber surface of film, so that smooth surface and/or film thickness is reduced to specific uniform thickness.Film at first stands mild compression and crosslinked, is used for ablating with the improvement material so that fiber surface is smooth.

The of the present invention the 3rd separately aspect, laser instrument is pointed to the fiber surface of film and is moved ablated surface with respect to it, so that smooth surface and/or film thickness is reduced to specific uniform thickness.Select wavelength, power and the pulse frequency of laser instrument, it will make fiber surface polish and ablated surface will be become suitable thickness.Film can at first stand mild compression and crosslinked, is used for ablating with the improvement material so that fiber surface is smooth.

The of the present invention the 4th separately aspect, the cattle pericardium of selection part at first at least is crosslinked, and is poured second cross-linked material with chain length then, to allow to stride across domain between big fibril.Then, compressive films, it is subsequently through adding medicated cap and borohydride reduction is processed.

The of the present invention the 5th separately aspect, the use all capable of being combined of any preceding method is to produce bigger advantage.

To the further understanding of character of the present invention and advantage be described below with claims in illustrate---especially when combining accompanying drawing to consider, identical parts have identical Ref. No. in said accompanying drawing.

Brief description

To explain the present invention, and other advantage and characteristic will be through presenting with reference to accompanying schematic figure, wherein at present:

Fig. 1 diagram is used for before forming lobule from tissue, preparing and measuring the order of the prior art step of cattle pericardium tissue thickness;

Fig. 2 is the perspective view of the representative embodiments of the Cardiac valve prosthesis made of the available tissue that is conditioned according to the application;

Fig. 3 is the perspective view that can be used for Fig. 2 artificial valve's support frame;

Fig. 4 is the plane graph of the lobule of valve shown in Figure 2;

Fig. 5 is connected the bottom perspective view with the valve leaflet structure that forms the lobule assembly with reinforcement outer rim (skirt);

Fig. 6 A is described in the side view of the exemplary Cardiac valve prosthesis that curls on the gasbag-type delivery catheter;

Fig. 6 B shows the artificial valve who is installed on the gasbag-type delivery catheter and is in Fig. 6 A of its expansion state;

Fig. 7 is a sketch map of pericardium being organized the order of adjusting with laser ablation;

Fig. 8 is the plane graph of valve leaflet, and it shows the reinforced region that is formed by the thickness uniform tissue of being close to the lobule bottom margin;

Fig. 9 is the edge view of valve leaflet, and it shows reinforced region;

Figure 10 is the plane graph of Cardiac valve prosthesis lobule, and said Cardiac valve prosthesis lobule penetrates with the zone that is connected with structure stand at stitching thread has the neighboring that thickens;

Figure 10 A and 10B are the footpath sectional views to the midline through Figure 10 lobule, and it shows the section of two different-thickness;

Figure 11 is the plane graph of Cardiac valve prosthesis lobule, and said Cardiac valve prosthesis lobule penetrates with the zone that is connected with structure stand at stitching thread has neighboring that thickens and the free edge that thickens, with the risk that reduces to prolong in this position;

Figure 11 A and 11B are the footpath sectional views to the midline through Figure 11 lobule, and it shows the section of two different-thickness;

Figure 12 is the plane graph of Cardiac valve prosthesis lobule, and said Cardiac valve prosthesis lobule penetrates to have with the zone that is connected with structure stand in neighboring that thickens and the free edge that is stimulating the A Langxiwusi brief summary at stitching thread has 3 zones that thicken;

Figure 12 A and 12B are the footpath sectional views to the midline through Figure 12 lobule, and it shows the section of two different-thickness;

The plane graph of the optional lobule of Figure 13 diagram, said optional lobule have the peripheral edge regions that thickens, along a plurality of radially bands that thicken that thicken band and extend to cusp edge from free edge of free edge;

Figure 14 A and 14B are the sketch maps that the exemplary lobule that utilizes profile to form model is cut segmentation method;

Figure 15 A is the sketch map of the dermatotome that cuts and organizes, and the result in the general section of Figure 15 B diagram pericardium tissue;

Figure 16 is the diagrammatic side view of compression, and wherein, near spacer is removed in order to know.

Detailed description of the preferred embodiment

In main embodiment, description is used for Cardiac valve prosthesis, the preparation of especially expansible valvular lobule.Lobule desirably is combined in the expansible Cardiac valve prosthesis; This expansible Cardiac valve prosthesis curl at first (perhaps even roll) become little section or the diameter sent with through conduit or other delivery system; At implantation site, typically be the expansion of valve annulus place then.Cardiac valve comprises the structure stand body, wherein combines a plurality of flexible leaflets.Multiple material is suitable for stake body, although some Ni-Ti alloy (that is Nitinol) is because their super-elasticity and biocompatibility and by preferably.Should also be noted that specific stake body structure is not considered to restrictive, and various CONSTRUCTED SPECIFICATIONs can be modified.

Although form the size of sending that thin Cardiac valve prosthesis lobule helps to reduce expansible valve, form than lobulus gracilis as described hereinly and regulate lobule and be considered to also have superiority for the conventional cardiac valve.For example, the rough surface of pericardium tissue is polished be considered to through reducing the ruggedness that loose fiber and the thrombosis of following improve lobule.

It is 0.014-0.023 inch (~ 350-580 micron) that ruggedness surpasses the valvular cattle pericardium lobule thickness range in 10 years, and wherein less valve utilization is than lobulus gracilis and bigger valve has thicker lobule.Current percutaneous valve can the little pig pericardium tissue to 0.004-0.005 inch (~ 100-130 micron) of used thickness.Although it is thin slightly that the porcine tissue of natural generation is compared with the pericardium tissue of natural generation, utilize the pericardium lobule to have some advantage.

Multiple tissue can be used for lobule, although the preferred tissue that uses is the Niu Tibi pericardium in the main application of heart valve leaflets.Though cattle pericardium thickness of tissue and intensity are considered to expect for more persistent valve, can use other bioprosthetic tissue such as pig, horse and other mammal---comprise people's pericardium.In addition, can use tissue, like dura mater, peritoneum (peritoneum), barrier film or other from other anatomy source.Have suitable ruggedness and elastic any tissue film all is candidate's a tissue as pericardium, can be more suitable for any one concrete application although it will be apparent to one skilled in the art that some material.Usually, comprise the fiber collagen protein, the tissue that especially is classified as I type or III collagen type and elastic fiber or elastin laminin can be suitable for preparing heart valve leaflets.Other of operable collagen protein possibly type be that blended natural collagen protein solution or electricity spin (electrospun) collagen protein elastin laminin fabric.Likewise, can use some so-called engineering tissue, they synthesize through collagen protein being organized in growing on typical screen frame frame or the stand (scaffold).These sources are collectively referred to as " tissue film ", and all can benefit from principle as herein described, although some similar bovine pericardium is particularly suitable for regulating the heart valve leaflets according to the application.

As stated, pericardial sac is made up of two or more different layers, and the one side of said layer is smooth relatively, and facing surfaces comprises the connective tissue that covers with fatty tissue, and some of them are peeled off when being obtained, and therefore it be fibrous.Method as herein described is useful especially for making fibrous face polish to form consistency of thickness and slick film.In some cases, the thickness of fibrofatty tissue's face also can be reduced, and is to produce uniform thin film, preferably below 300 microns, collapsible to be used for/expansible valve.

With reference to figure 2, show that exemplary monolithic (one-piece) Cardiac valve prosthesis 50 can utilize the cattle film with uniform thickness.To a certain degree describe valve 50 in detail; So that some benefit of lobule manufacturing approach described herein to be described; But find on June 8th, 2009 of the U.S. Patent Publication can submit to to(for) the more details of valve structure number 2010/0036484; Its name is called " LOW PROFILE TRANSCATHETER HEART VALVE ", and is transferred Edwards Lifesciences, and its disclosure is merged in this paper by reference.Alternatively; Can utilize the U.S. Patent number 6 of another Wicresoft's valve of thin pericardium in distribution on May 11st, 2004; 733; Find in 525, its name is called " ROLLED MINIMALLY INVASIVE HEART VALVES AND METHODS OF USE ", and its disclosure is incorporated into this paper by reference clearly.

Valve 50 in the illustrated embodiment generally comprises structural framing or support 52, by the flexible leaflets structure 54 of frame supported be fixed to the pliable and tough outer rim 56 of leaflet structure outer surface.Diagrammatic valve 50 can be implanted in the ring of natural aortic valve film, but also can be suitable for being implanted in other natural valve of heart or in various other pipes or hole of health.Valve 50 has " lower " or flows into end 60 and " top " or outflow end 62.Blood makes progress free-flow through valve 50, but the downward adverse current of flexible leaflets structure 54 close preventing.Therefore flexible leaflets structure 54 provides flexible mobile confining surface (occluding surface), makes the blood can one-way flow.

Valve 50 and framework 52 are configured to state that but radial folding becomes to fold or that curl, on delivery catheter, being incorporated into health, but and radial dilatation to the state of expansion, with the position (for example, natural aortic valve film) that valve is implanted to the health desired.Framework 52 can be processed by plasticity-expansible (plastically-expandable) material, and said material allows valve to be curled into than small section, sends and expands valve with the air bag that utilizes extension fixture such as balloon catheter.Exemplary plasticity-expansible material is including, but not limited to rustless steel, nickel-base alloy (for example, nickel-cobalt-chromium alloy), polymer or its combination.Alternatively, valve 50 can be the so-called self expandable valve that its middle frame is processed by self expandable (self-expanding) material such as Nitinol (Nitinol).The self expandable valve can curl and keep being in folded state with restraint device (restraining device) like the sheath (sheath) that covers valve.When valve is positioned near target site or its, can remove restraint device, become the functional dimension of its expansion to allow the valve self expandable.

Also with reference to figure 3 (in order to explain, it is display frame only), framework 52 is general tubulose, scaffold-like structure, and it has pillar a plurality of angled intervals, vertically extending (strut) or engages connecting rod (post) 64.The reader will notice, some modification a little that the bar 64 among Fig. 3 and Fig. 2 are shown, and difference is very little.The pillar 66 that bar 64 extends through the plurality of rows periphery interconnects.Occupy and engage connecting rod 64 intermediary thin vertical (axially) bars 68 and be connected with the pillar 66 of the horizontally-arranged that is close to and between it, extend.Each row's pillar is " it " font or the roughly crenellation pattern arrangement to extend in the framework peripheral direction as shown desirably.Pillar contiguous in the same row is interconnected with one another as shown, with angulation when extending, desirably between about 90 and 110 degree.This makes the radial strength optimization of framework 52 when expansion, and still allows framework 52 to curl equably, expands with the mode that describes below then.

Leaflet structure 54 desirably comprises three lobules 70 that connect separately, such as shown in Figure 4, its can be aligned to Tricuspid valve arrange folding (shrinkage, collapse), like best image in Fig. 2 and 5.Each lobule 70 all have the bendings low cusp edge 72 relative with the top free edge of straight 74 and at free edge 74 and two of extending between than low edge 72 engage flap (flap) 76.Crooked cusp edge 72 forms single sector region (scallop) in leaflet structure 54.When being fixed to two other lobules 70 when forming leaflet structure 54, the bent tip edge of lobule 72 is common form leaflet structures fan-shaped than low edge (like best image in Fig. 5).Like what in Fig. 4, further show, two stiffeners 78 can be fixed to each lobule 70 (for example, utilizing stitching thread) that is adjacent to flap 76.Then, flap can fold on bar 78 and utilize stitching thread to be fixed in the folding position.If expectation, each bar 78 all can be placed in the protective casing (sleeve) (for example, the PET sleeve pipe), is fixed to lobule then.

Lobule 70 interconnects to form the joint 80 (seeing the edge that Fig. 2 lobule gathers together) of leaflet structure at its vicinal face.Leaflet structure 54 can utilize various technology and mechanism to be fixed to framework 52.For example, like best image in Fig. 2, the joint 80 of leaflet structure desirably is in line with support bar 64 and utilizes stitching thread to pass through hole 82 (Fig. 3) and is fixed to the upper.The junction point of lobule and bar 64 can be strengthened through bar (bar) 78 (Fig. 4), is desirably processed like rustless steel by hard relatively material (comparing with lobule) for said 78.

As described, leaflet structure 54 desirably have corrugated, bent fan than low edge.Visible stitching thread 84 is followed the fan-shaped of (track) leaflet structure 54 on the outside of the outer rim 56 of Fig. 2.Through forming lobule with this fan-shaped geometry, the stress on the lobule is reduced, and this improves the ruggedness of valve conversely.In addition,---it can cause the early stage calcification in these zones---can be eliminated or be minimized at least by means of fan-shaped, at the folding line (fold) and the pleat (ripple) of each lobule abdominal part (central area of each lobule).Fan-shaped geometry also reduces the amount of the organization material that is used to form leaflet structure, thereby allows to flow into the less of end at valve, even the section that more curls.

Refer again to Fig. 2 and 5, outer rim 56 can, for example form by PET (PET) ribbon.Leaflet structure 54 is connected with outer rim through thin PET reinforcing band 88 (or sleeve pipe), Fig. 5, and this makes it possible to fix stitching and protects the pericardium tissue of leaflet structure to avoid breaking.Leaflet structure 54 is sandwiched between outer rim 56 and the reinforcing band 88.Stitching thread 84---is sewn onto outer rim 56 with reinforcing band and leaflet structure 54---, and can be the stitching thread of any appropriate, it desirably follows the sweep of leaflet structure 54 bottom margins, as being seen on the outside of the outer rim 56 of Fig. 2.Outer rim 56 also is fixed to horizontal strut 66 through the stitching thread 86 of a succession of " it " font pattern with leaflet structure 54 assemblies in framework 52, as shown in Figure 2.

In order to assemble, heart valve leaflets 70 is cut down such as bovine pericardium from film, and according to principle as herein described with its attenuation, adjusting or otherwise carry out plastotype.In above-mentioned expansible valve 50, lobule 70 is connected in the tubular bracket framework 52, and the free edge 74 of three pairs of vicinities is set in the middle of the valve at the joint line place that relative to each other waits angular orientation.Free edge 74 is inwardly heaved (billow), to gather along joint line.Then, the valve of assembling is stored in before implantation in the sterile liquid, is generally glutaraldehyde, a period of time.

Fig. 6 A is presented at the Cardiac valve prosthesis 50 that curls on the air bag 92 of gasbag-type delivery catheter 90.Illustrated like this paper, the attenuation that is applied to the bioprosthetic tissue of lobule material helps to make the overall diameter D of valve and balloon catheter of assembling little of 6mm.The Cardiac valve prosthesis size of expansion usually on the 20mm between about 30mm Anywhere.

Fig. 6 B shows optional embodiment of the artificial valve 100, and it comprises framework 102 and the leaflet structure 104 (for example, utilizing the stitching thread that as above shows and describe) that is installed in the framework.Show that valve 100 is in its expansion state after expanded balloon 92 has expanded.The size of valve 100 of expansion changes according to the patient, usually 22 and 40mm between.

Implantation method comprises with obvious amount radial compression valve 50, reducing its diameter or to send section, valve is inserted into means of delivery such as conduit or intubate and means of delivery is advanced to anatomical location correct in the heart.After suitably being arranged, valve 50 launches through radially expanding in the natural valve ring with expanded balloon 92.Folding valve 50 can be through vascular system such as being introduced into through femoral artery in the conduit, or more directly, and the intercostal otch through in the heart is introduced into.Valve is as much as possible for a short time to be important.Big valve needs large diameter conduit, and it is difficult to promote process, for example femoral artery.For the cardiac valve that makes contraction is littler, maker will be used to make the attenuation of organizing of lobule 70.Preferably, regulate and to comprise and reduce tissue thickness, but also can comprise tissue is polished to produce film thin, that thickness is constant, from this film cutting time lobule.Perhaps, lobule can at first be formed then by attenuation.Exist some to make the method for organizing attenuation, comprise the laser ablation of explanation below utilizing.

Should notice once more that the pericardium of attenuation described herein can be used for various types of cardiac valve, comprise conventional surgical operation valve.This method also can be used for only making tissue surface to polish or " repairerment " tissue surface, to eliminate the thrombosis agent such as the fiber that dangles, and can perceptible attenuation and have no.This tissue that polishes is---still thick relatively---to be can be used in the conventional surgical operation cardiac valve.Can utilize an instantiation according to the conventional cardiac valve of tissue of the present invention is pericardium bioprosthesis

series (line), can obtain from Edwards Lifesciences.The basic structure of

valve is shown in U.S. Patent number 5; 928; 281, its disclosure is incorporated into this paper by reference clearly.

Desirably, be used for pericardium layer scope through the catheter heart valves lobule at the 250-500 micron, and preferably more approach 250 microns.Unfortunately, only the pericardium of minority acquisition approaches 250 microns thickness.Most materials is the 300-700 micron.As a result, each pericardial sac only produces about 1-2 lobule that is suitable for THV.Yet, is used to make up valvular pericardium tissue and forms, and most of collagen fabric is parallel between layer by a plurality of organized layers with similar component.This particular structure makes it can use various means, and for example laser instrument, razor remove some tissues.Expect removed tissue from fibrous face, be removed from this fibrous face before the fatty tissue.This produces clearer and more definite, thinner pericardium, and it has the low section that is more suitable for.

Along with the arrival of laser technology, the ablation of cornea tissue becomes common.Excimer laser (excimer laser) has been used to such program.With reference to U.S. Patent number 4,840,175.Nearest parts (work) with the mode-locked laser that in psec and femtosecond scope, has very short pulse length also are considered to reduce heating.Laser also is used to cut and organize, and the cardiac muscle that is used for ablating is with the treatment arrhythmia and be used for dental applications.Be used for two other disclosures of purposes that the people organizes removal in the U.S. Patent number 7,367,969 of the U.S. Patent number of Holha 7,022,119 and Stoltz etc. about laser.These reference laser light documents are merged in this paper by reference.Utilize the laser ablation of laser assisted in-situ corneal refractive implantation method also to be suggested the thickness that reduces bovine pericardium is used for various uses with generation membrane tissue; Said purposes comprises the cardiac valve in the U.S. Patent Publication number 2007/0254005, and its disclosure is merged in this paper by reference.

Fig. 7 schematically shows bioprosthetic tissue in the preparation of ablating to make the order of implant assembly such as the incident of heart valve leaflets.Be used for the pericardium material that the heart is implanted in order to prepare, the film 110 of the removed cattle pericardium of a large amount of outside fat/fatty tissuees is selected, and its thickness is 250 microns or thicker (usually in the scope of 300-700 micron).---inner surface of forming pericardial sac in the body---still is attached with some outside fat/fatty tissuees 114 to be presented at following collagen layer 112.

Tissue ablation can be passed through, and for example film 110 exposes with plane form and accomplishes, as illustrated by the flow chart of Fig. 7.In planar configuration, film 110 is fixed or remains in the suitable plane.Laser instrument 116 points to the top fiber surface 114 of films 110, and the focus that wherein is used to ablate by adjustment is in the top or the vicinity of collagen layer 112.Alternatively, although do not show that film 110 can be disposed on the live spindle, so that contiguous laser can be removed tissue.Consider to be used to produce other physique that relative organization/laser instrument moves.Laser instrument 116 and surface relatively moving between 114 cause then the ablating material of film 110.According to the transparency of membrane tissue, need a more than uniform thickness that path is realized expecting to laser beam.

Useful laser instrument specification comprises in the heart valve leaflets: the twin shaft scanning lens to produce at the ablation pericardium in discovery; The expansion of 2 * bundle; The 1550nm wavelength; 31.5 μ J pulse energies to target; 1.6W mean power; The 50Hz repetition rate; 650fs pulse width (ref); 30 μ m laser spots size; Elliptical polarization; The 112mm focal length; 400mm/s corase grind speed (20 μ m fill spacing in cross hatch pattern (cross hatch pattern)); With 800mm/s fine grinding speed (20 μ m fill spacing in the cross hatch pattern).

The a large amount of technology that are used for high precision guidance laser and ablation tissue have been developed.Cornea is ablated and was extensively implemented nearly 20 years.Utilize this technology of excimer laser to become common.Refer again to U.S. Patent number 4,840,175, its disclosure is merged in this paper by reference.Have and reduce heating has the mode-locked laser of the pulse length of lacking very much in psec and femtosecond scope nearest parts and be studied.

Being used for this machine of milling that is not directed against patient's accurate parts also can obtain.Application has above-mentioned specification laser instrument as have 2-axle scan laser head, tissue fixator (tissue holder) to be written into mechanism to help that parts are loaded into machine, X-Y platform (table) with the work area that increases laser instrument and tissue fixator automatically for the mill utensil of handling the useful operation tool of pericardium easily.The pericardium that said mechanism can be used for optionally ablating and install has the style of different-thickness with generation, the following argumentation.

The machine of milling is operated according to the input data that limit otch style and roughness automatically.Typically, this machine is arranged, with the concrete height control notch depth according to the surface that is cut.Through this arrangement, the profile of precut will be reflected in the gained surface.For fear of such result, the surface height that can use fixed reference substance (reference) rather than be cut.By this way, the complete style on the parts will be arranged in the plane with each complete cut.Then, a plurality of otch are used to realize the film thickness expected.

Enough pack closely for the suitable life-span and the realization that keep the pericardium lobule, put in place, need the lobule of particular organization's thickness to be inserted into through femoral artery.For example, find that 250 microns uniform thickness is particularly useful, although the uniform thickness between the 250-500 micron possibly be suitable.Select wavelength, power and the pulse frequency of laser instrument 116,120, it will make fiber surface polish, to eliminate the thrombosis agent and ablated surface is become suitable thickness.Various wavelength all can be adapted to this method and not produce excessive heat, also are effective simultaneously.If the use ultra-short pulse laser believes that optical maser wavelength does not change the result significantly.Utilized the 1550nm wavelength to prepare the lobule sample.

This method for preparing can increase the output from the cardiac valve leaflet of pericardium.In fact, utilize this paper disclosed method, expection can obtain 5 heart valve leaflets at least from each pericardial sac.

If in stem organization, carry out, the laser ablation of pericardium is understood that to have superiority.This can through at first with glutaraldehyde or equivalent use based on the processing fixed sample 110 of glycerin and before laser ablation dry tissue accomplish.This drying means based on glycerin is disclosed in 1 day May in 2008 of Tian etc. in the U.S. Patent No. publication number 2008/0102,439, and its disclosure is merged in this paper by reference.

Except producing single uniform thickness, method as herein described also can be used for optionally making organizing attenuation, to obtain to have evenly but the zone of different-thickness.A useful especially instance is presented among Fig. 8, and this figure shows heart valve leaflets 130, and it has outer regions 132, and is thicker than the remaining area 134 of lobule.Especially, the low bending or the cusp edge of lobule can be thickened, so that be fixed to above-mentioned outer rim 56 after a while.The zone 132 that thickens desirably comprises roughly the evenly band of width.This is similar to as described above fixedly reinforcing band 88, and two kinds of technology all can be used for even bigger reinforcement.Can prepare three such lobules 130 in the same manner, then, arrange with Tricuspid valve in its trip edge it is connected to each other, forming leaflet structure, as Fig. 2 and 5 54 shown in.Common band or the sleeve pipes of limiting of reinforced region 132 on the lobule, it partly extends than low edge along the inner surface of leaflet structure 54.

Fig. 9 diagram has the edge view (edge view) that stress slows down the lobule 130 of section, and this lobule has reinforced region 132, from slowly carry out the transition to the thin major part 134 of lobule 130 like sloping 136 visible thickness.Reinforced region 132 is coarse a little by diagram, with simulation microscope structural heterogenity, although utilize some technology as herein described can make identical surface more smooth.Reinforced region 132 can limit maximum lobule thickness T _Max, between about 300-700 micron, and thin main region 134 desirably has minimum lobule thickness T _Min, between about 200-500 micron, and maybe be thinner.More specifically, to 17 or the less cardiac valve of 19mm, consider minimum thickness T for little _MinLeaflet tissue between the 150-250 micron, and big valve can have the tissue of going up to 350 microns like the 26mm valve.The embodiment of a consideration is that the order of magnitude is merely 100 microns ultra-thin tissue.Maximum lobule thickness T _MaxDesirably approach the twice of segment thickness up to lobule.In instantiation, the less valve of 19mm can have such lobule, its T _MinBetween the 150-250 micron, maximum lobule thickness T of while _MaxIn the zone of strengthening up to the 300-500 micron.

Figure 10-12 diagram is organized the optional thickness profile in the artificial heart valve leaflets from the pericardium of selectivity attenuation method as herein described.Each lobule all shows with plane graph, and it has the free edge 142 of arc cusp edge 140, the straight relative with cusp edge and at the outthrust (tab) 144 of a pair of relative orientation of the arbitrary end of free edge.Each outthrust 144 includes gradually sharp side 146, and it carries out the transition to free edge 142.Core 148 in each lobule forms mobile confining surface, and it advances vibration and go out flow, to open and close valve alternatively.This shape only is exemplary, and other lobule shape is known.Each lobule that shows among Figure 10-12 all is of similar shape, and therefore will use the components identical numbering to shape facility.

Figure 10 diagram lobule 150, it penetrates with the zone that is connected (not shown) with structure stand at stitching thread has the peripheral edge regions 152 that thickens.More specifically, the peripheral edge regions that thickens 152 around whole cusp edge 140 extend and on reach at least a portion of outthrust 144.As described, these are that wherein stitching thread is used to connect the zone of lobule to supporting bracket.The thickness of peripheral edge regions 152 could be up to 700 microns, preferably between the 300-700 micron.Simultaneously, form center part 148, it has relatively little thickness, thereby helps the less section of sending of compressed thin film.For example, it is particularly useful that 250 microns uniform thickness of core 148 is considered to the curling section of/expansible valve collapsible for reducing, although uniform thickness possibly be suitable between the 250-500 micron.

Figure 10 A and 10B are process Figure 10 lobule footpath sectional views of (vertical) to the midline, and it shows the section of two kinds of different-thickness.In Figure 10 A, (step) 154 carries out the transition to thin core 148 to thicker peripheral edge regions 152 on steep relatively rank.On the contrary, the gentle slope 156 between Figure 10 B diagram back edge zone 152 and the thin core 148.Show that slope 156 is linear, although other profile is such as crooked or can be used by rank.Believe that more slow slope 156 provides the stress distribution of more expectation and flowing on lobule.Possibly use through the adjustment laser power transition gradually is provided.The other type that realizes the gentle slope is to use cuts the technology of cutting and combines to form model, as through being described below with reference to figure 14A and 14B.

Figure 11 is the plane graph of Cardiac valve prosthesis lobule 158, its have the peripheral edge regions that thickens 152 shown in figure 10 and along free edge 142 thicken be with 160.Cardiac valve prosthesis destroys owing to the set of lobule wherein or the lobule free edge that is bonded together prolong sometimes, and this finally can cause the valve prolapsus.Provide along whole free edge 142 thicken with 160 risks that reduce to prolong, because stress and its thickness of free edge experience are proportional.Figure 11 A and 11B show the section of two different-thickness of Figure 11 lobule once more, wherein, the peripheral edge regions that thickens 152 with thicken with 160 can be on rank 162 (Figure 11 A) or gentle slope 164 (Figure 11 B) locate to carry out the transition to thin central area 148.

At last, Figure 12 diagram heart valve leaflets once more 166, it has the neighboring 152 that thickens in the zone that is used for the syndeton heart valve bracket.In addition, lobule 166 has 3 zones 168 that thicken in the centre of the free edge 142 of simulation A Langxiwusi brief summary.For clear, in heart valve leaflets so-called 3 be lobule at the flow ports center with the gather together point of (joint) of other lobule.Because three lobules to bent intermediate, possibly be enough to cause backflow in 3 spaces of locating therebetween.In native leaflet, the center of free edge has the zone that thickens sometimes, is called as the A Langxiwusi brief summary, and it often fills 3 spaces of locating.When the pericardium tissue that uses uniform thickness is used for lobule, only can avoid seepage through composition surface with the length that needs extra lobule material.Yet, influence the ability that valve is compressed into low section so unfriendly, and, cause lobule when closing, to be out of shape sometimes, this can cause early stage calcification.Through in each lobule, producing 3 zones 168 that thicken, can simulate the A Langxiwusi brief summary.Exemplary 3 zones 168 are shown as the little triangle at free edge 142 centers, although shape can be crooked, like semicircle or other shape.In addition, 3 zones 168 can be along free edge 142 and 162 combinations of being with that thicken, as visible in Figure 11.In fact, any various zones that thicken as herein described all can be made up with other zone for desired effects.

Figure 12 A and 12B show the section of two kinds of different-thickness of lobule 166.Figure 12 A show thin core 148 and the neighboring 152 that thickens and 3 zones 168 thickening between steep rank, and Figure 12 B is presented at the slow transition of same position.

Figure 13 diagram the application's optional lobule 170, it is sagging that it can help to reduce lobule, and this is found to be the reason of some Cardiac valve prosthesis failure.The opposing that lobule is prolonged is with directly proportional along the little leaf thickness of radial stress line.Therefore, except the peripheral edge regions 152 that thickens and along free edge 142 thicken be with 160, lobule 170 also comprise a plurality of thicken radially be with 172,174, it approximately extends to arc cusp edge 140 from the center of free edge 142." RADIAL " is the edge of central circular as cusp edge 140 for the centre with free edge 142 by being drawn on this meaning, although should be appreciated that, cusp edge 140 can not limited by single arc, and can be or not the center of free edge 142.Typically, yet prosthetic leaflet is symmetric around the footpath to the midline, therefore, one preferred arrange comprise along center line (vertical) thicken radially with 172 and radially be with 174 what 172 arbitrary of belts symmetric thickened.In diagrammatic embodiment, three bands are arranged: middle tape 172 with approximately become two of 30 ° of angles with middle tape and radially be with 174.Should also be noted that like institute diagrammaticly, have approximately identical width around each band that thickens of lobule, although must not be this situation.For example, cusp edge band 160 and radially can be basically thinner than the marginal area 152 of the essential process of stitching thread with 172,174.

As stated, profile forms model and is used in the varied in thickness that produces in the lobule as herein described gradually.Figure 14 A and 14B utilize the exemplary lobule of this model to cut the sketch map of segmentation method.In Figure 14 A, form model 176 and comprise the lobule stayed surface, it has a side 178 lower than another side (side) 180.The instrument of milling like laser instrument 182 process on the upper face of lobule 184, and can be controlled, to remove material to the predetermined reference plane.By this way, it is thicker that the left hand edge of lobule keeps, and more material is removed from the right side, to produce thin lobule zone in this position.In Figure 14 B, second forms model 186 comprises the lobule stayed surface, and it has the periphery side 188 lower than mid portion 189.Once more, when laser instrument 182 on the upper face of lobule 184 through out-of-date, it is controlled, and makes it be low to moderate reference plane to remove material, more material will be removed from the central area of lobule.Certainly, consider to form the many different shape of model, it only is exemplary being illustrated among Figure 14 A and the 14B those.

The uniform film of gained preferably be processed so that its roughly inertia (inert), be used for the people safely and transplant.Processing generally includes immerses chemical solution such as glutaraldehyde with film and reaches the preset time section, with tissue or " pathogenic bacteria " of removing the microorganism entity.Exemplary isolation period, be about 14 days.Alternatively or in addition, the film of completion can utilize and add medicated cap calcification nucleation site and borohydride reduction and be processed, to alleviate calcification in the body after a while.

For example, a kind of order of adjusting tissue of consideration comprises: at first, make tissue (for example, bovine pericardium) and glutaraldehyde buffer solution crosslinked.Next, can utilize, middle disclosed method will be organized heat treated like the U.S. Patent number 5,931,969---its disclosure is clearly incorporated into this paper by reference---at the Carpentier of on August 3rd, 1999 distribution.Subsequently, can utilize that disclosed any method reduces tissue thickness among the application.At last, can handle with adding medicated cap and/or Reducing agent than thin tissue, to alleviate calcification in the body after a while, this also can comprise with glycerin/alcoholic solution handles.For the Cardiac valve prosthesis lobule, organize and form lobule then, be connected to cardiac valve support frame or other the such assembly that centers on and use such as ethylene oxide sterilizing.To organize grinding, smash to pieces, section, laser ablation, stretching (drawn down) or extruding to be reducing after its thickness, calcification nucleation site (for example, aldehyde and Schiff bases) can be exposed, this produces the tendency of calcification.Handle and to make nucleation site add medicated cap and keep the collagen protein integrity with adding medicated cap agent (for example, ethanolamine) Reducing agent (for example, sodium borohydride) and collagen protein antiseptic (for example, glycerin).It is in the past durable that this allows tissue to reduce as its thickness.In addition, this method also will allow tissue to be stored in on-liquid (that is the glutaraldehyde) environment.In other words, this method stored dry of being particularly suited for organizing.

As stated, film can partial cross-linked at least or " fixing ".The crosslinked with collagen albumen substrate provides stability before transplanting, with delay degradation.In addition, fixing means is operated with inner reactive molecule through the surface that hinders donor tissue usually, thereby makes it have basically no antigenicity and be suitable for transplanting.Fixed biologically prosthese tissue generally includes and makes tissue and cross-linking agent, and---normally being solution---contacts.The example fixed solution that is used for bioprosthetic tissue such as bovine pericardium comprises glutaraldehyde, formaldehyde, other aldehyde, EDC, Polyethylene Glycol etc.The alternate manner that has fixing organization comprises heating, irradiation etc.Help to keep pericardium to be in specific three dimensional form if fixing step can be produced the back with other mode at film---adopt.

Should be appreciated that although crosslinked tissue causes than is easier to handling workpiece, attenuation also can take place before crosslinked.Likewise, the bulk tissue sheet can be in the at first attenuation of fixing front or rear quilt, and perhaps lobule can at first cut down from the bulk film, then in fixing front or rear attenuation

Except above-mentioned laser tissue was removed, various machinerys such as the razor or the planing device that are used to shear tissue can also be used to remove some tissues.For example, the device that has a flat clamp (platen) of planing razor or blade translation above that can replace the linear laser device structure of Fig. 7.Also consider to be used to produce other physique that relative organization/razor moves, the outer surface of tissue is polished as for example utilizing lathe appearance razor.Each of these devices all can utilize optical surface to measure assembly by automatic control or by computer control, with the degree of depth of control otch.(for example, sand milling or file) removed by tissue abrasion also can prove suitable, although the gravel of instrument should be trickle relatively.

Being used to make the instrument of the attracting especially mechanical system of pericardium tissue attenuation is dermatotome.Be used to obtain the skin thin slice in the operation of dermatotome orthopaedic surgical operations,, be particularly useful for 3 grades of burns or damage to be used for skin transplantation from donor areas.These devices start from nineteen thirties, and they are Surigical tools of knowing knowledge.Dermatotome is by manually, pneumatic or electric operating.The uniformity of the skin thickness that is used to transplant is unimportant for the degree of heart valve leaflets needs.

Figure 15 A and 15B diagram dermatotome 192, its common section from the pericardium tissue is cut and is cut rough layer.Be not to obtain material sheet, but the material of removing through dermatotome 192 190 is dropped the pericardium 194 that is beneficial to be left as heart valve leaflets from film.In order to reach reliable sheet thickness, use spacer 196, dermatotome 192 moves above that.Cutting the surfacing 190 that cuts from film 194 is fibrous face of pericardium.Film is placed on the rubber backboard 198 and is clamped.Backboard has spacer 196 at the either side mask of film, and it serves as track when dermatotome 192 passes film 194, to support dermatotome 192.Dermatotome 192 also can be controlled, and cuts into the expectation style with restriction, so that can produce the zone with differing heights.Advantageously, utilize machinery to produce uniform thickness and in pericardium, do not produce heat or chemical action.Should be appreciated that as used herein, term " dermatotome " is meant that dermatotome, vibratome or any other function class are similar to the machine cuts or the milling device of the conventional dermatotome that is used to shear tissue.

Reflect the precut profile for the surface that overcomes the laser ablation gained with other type, can use first compression pericardium.Be enough to that surface imperfection is flattened and realize that more the compression of homogeneous thickness can be carried out before laser ablation.Surface imperfection is flattened help to guarantee that laser ablation step causes removing more equably the surface.On the contrary, do not compress, laser operation can be followed the profile of irregular surface and remove the material of same amount in its surface, produces irregular end product.Guarantee that regular initial surface is that the reference journey of utilizing indication laser to remove material with respect to fixed, uniform surface level is come the preface control laser instrument of milling with ablated a kind of other method of mode that produces smooth surface, this is with to follow the surface profile of being milled opposite.

Typical pericardium tissue is in balance with about 78% water; And water can be extruded from tissue.For realizing that fiber surface flattens and the excess compression of homogeneous thickness more can make the elongation of collagen protein polymer backbone and destroy, eliminate collagen protein " curl " structure and the inherent biological elasticity of disorganize.Yet, do not exceed yield point and allow inherent biological elasticity as time passes and resilience.In the elastic compression lower part or be completely fixed the advantageous effect that pericardium can keep laser ablation between compression period.Even with appropriate less compression, some conjugates (bonds) also can be destroyed, and produce some free aldehyde, amine and acidic-group.Through with the fixing pericardium of this gentle compressive state, conjugate is produced to keep this state.Alternatively, pericardium is tending towards not fully resilience immediately.Carry out laser ablation after the compression immediately and can alleviate the elasticity further expansion.

Alternatively, can use and at first regulate the surface irregularity order of compress tissue film then.For example, the big surface imperfection on the pericardium tissue fibers face can utilize laser instrument, mill or dermatotome to polish, and then, utilizes the whole bag of tricks compress tissue as herein described.Preferably, the compress tissue while is the partial fixing tissue at least, to help prevent resilience.This order can produce more mechanical uniform formation structure.

As stated, gentle compression simultaneously under compressive state fixedly pericardium the fiber surface of pericardium is polished and make thickness more even.This compression and fixing can carrying out before or after organizing attenuation making.After attenuation, utilize the stabilizing step that adds medicated cap and borohydride reduction can alleviate calcification in the body after a while.

Under ablation or processing method existence or non-existent situation, even bigger compression also is possible.If use laser ablation or processing method, it is less important to be organized in the degree that is fixed after the compression, because use physics correction rather than further compression.If fixing by fully at first, it is perfectly elastic that then gentle compression, further compression are tending towards, only if tissue is damaged.Carry out partial fixing with gentleness compression and carry out further fixed method with bigger compression then and can be used for obtaining thin telolemma, it has tangible hot strength.

Consider initial gentle compression and fixing step above.This method yet can not have initial gentle compression but carrying out under the situation of initial partial fixing tissue at least.Once more, can use glutaraldehyde or other fixative or method.The biomechanics of this at first fixed order stabilizing tissue is also protected natural " curling " structure of collagen protein.Second immobilization material that perfusion has enough chain lengths is to allow to stride across domain between big fibril, and this can produce stable film then.Can use to have two of enough chain lengths-or the polyamines material.Stride across between big fibril other cross-linked material of domain and comprise linear and ramose polyaziridine, polyvinyl alcohol and various polyetheramine (Jeffamine) polymer simultaneously.Alternatively, tissue can be used, and for example sodium chlorite oxidation changes into carboxylic acid with the aldehyde that will newly form.These can utilize EDC chemistry art and above-mentioned amine coupling then.When compression can occur in method and begins, or after occurring in perfusion second immobilization material, perhaps both all take place.Laser ablation or processing can be inserted suddenly after compression step and/or after first fixing step, so that the smooth or further attenuation that becomes.After first fixing step, these tissues can be added medicated cap and reduction, and perhaps alternatively, compression and crosslinked tissue can be through adding medicated cap and borohydride reduction by stable after forming process.Further processing can comprise drying and sterilization.Such processing is described in the U.S. Patent Publication 2009/0164005 of disclosed, Dove on June 25th, 2009 etc., and its disclosure is incorporated into this paper by reference clearly.

The equipment that uses in arbitrary or all compression steps is illustrated among Figure 16.Porous ceramics pressure plare 200,202 is used to the rigidity compression to tissue 204 is provided.Dialyzer 206,208 is inserted into plate 200,202 and organizes between 204.Ceramic pressure plate 200,202 allows various chemical treatments (treatment) freely to be recycled in the tissue 204.Disposable dialyzer 206,208 be used to prevent ceramic pressure plate 200,202 stop up, to prevent flow of solution at production period.Tissue 204 either sides, porous ceramics pressure plare 200, spacer 210 limit compression between 202.

The Another Application of attenuation described herein and control method is that said pericardium sheet is processed by cattle or Cor Equi peplos in pericardium sheet (patch) field.The pericardium flake products can be as the structural material of tissue repair, and like aorta conduit, pericardium, blood vessel etc., it is very general in the pediatric patients of suffering from the congenital cardiovascular disease.A kind of so commercial cattle pericardium sheet can obtain from Edwards Lifesciences, its be of a size of 4 * 6 inches (10 * 15cm), although the horse sheet can littler (3 * 4 inches).The pericardium flake products is used usually with the similar method of heart valve leaflets and is handled (can be slightly different for the horse sheet).A problem is arranged, and promptly the pericardium sheet maybe be too thick for some this application, and institute can obviously provide its adaptability so that sheet is thinner equably.Likewise, usually there is the variation of thickness in fact between sheet and in the diverse location in any given.The uniform thickness scope of the expectation of final products can be 150 to 500 microns, and this depends on the size of flake products.Above-mentioned selectivity attenuation also can help sheet, and one of them edge or whole outer periderm more heavy back form to help keeping grappling to sew up.

Therefore, disclose preparation and be used for improving one's methods of pericardium material that the heart implants.Though embodiment of the present invention is shown and describes with using; But it will be evident to one skilled in the art that; Under the situation of the invention principle that does not deviate from this paper, many more modifications are possible, and; Should be appreciated that the term that has been used is descriptive rather than restrictive term.Therefore, can change within the scope of the appended claims and do not deviate from true scope of the present invention.

Claims

1. prepare the method for bioprosthetic tissue membrane material, comprising:

Selection has the tissue film of fibrous face and shiny surface; With

Remove material from the said fibrous face of the film of said selection, to reduce selected zone but the film thickness in the not all zone and said fibrous face is polished.

2. the described method of claim 1, wherein said tissue film is the cattle pericardium.

3. the described method of claim 1, wherein said removal step is accomplished through shearing with machinery.

4. the described method of claim 1, wherein said removal step is through accomplishing with laser ablation.

5. the described method of claim 1 also comprises

Tissue film through compressing said selection and compression down crosslinked said membrane material of while regulate the film of said selection.

6. the described method of claim 1 also comprises through adding medicated cap and handles the said film that thickness reduces.

7. the described method of claim 1 also comprises through borohydride reduction and handles the said film that thickness reduces.

8. the described method of claim 1 also is included in before the said removal step film of the said selection of partial fixing at least.

9. prepare the method for bioprosthetic tissue membrane material, comprising:

Selection has the tissue film of fibrous face and shiny surface;

Through the tissue film that compresses and crosslinked said film of while is regulated said selection under compression; With

Remove the material that is conditioned from the fibrous face of the tissue film of said selection, to reduce selected zone but the film thickness in the not all zone and make said fibrous face smooth.

10. the described method of claim 9, wherein said tissue film is the cattle pericardium.

11. the described method of claim 9 also comprises through adding medicated cap and handles the said film that thickness reduces.

12. the described method of claim 9 also comprises through borohydride reduction and handles the said film that thickness reduces.

13. the described method of claim 9, wherein said removal step is accomplished through shearing with machinery.

14. the described method of claim 9, wherein said removal step is accomplished through the material that is conditioned with laser ablation.

15. cardiac valve comprises a plurality of lobules, each lobule is processed by lamellar structure, and said lamellar structure has first area with uniform first thickness and the second area with uniform second thickness, and said second thickness is greater than said first thickness.

16. the described cardiac valve of claim 15, wherein each lobule has the cusp edge relative with free edge, and said second area is with the said cusp edge extension in the band edge of overall evenly width.

17. the described cardiac valve of claim 15, wherein each lobule has the cusp edge relative with free edge, and said second area also extends along said free edge with the band of overall evenly width.

18. the described cardiac valve of claim 15, wherein each lobule has the cusp edge relative with free edge, and said second area radially extends to said cusp edge from the center of said free edge with the overall evenly band of width.

19. the described cardiac valve of claim 15, wherein the transition between the thickness in first and second zones is gradually.

20. the described cardiac valve of claim 15 also comprises support frame, the neighboring of said lobule is connected with it with stitching thread, and wherein said second area extends the said leaflet edge of said stitching thread process along said leaflet edge.